Failure of beta (B) cell compensation for insulin resistance in humans leads to the progression to overt diabetes and its associated kidney, eye, vasculature and nervous system complications. During the previous funding period, we discovered that Pdxl, a pancreatic homeodomain transcription factor mutated in human type 2 diabetes, is required for li cell compensation for diet-induced insulin resistance in mice. Pdx1*'' mice stressed by a high fat diet fail to increase insulin secretion or to expand B cell mass due to increased Q> cell death and decreased li cell hypertrophy. We determined genome wide Pdxl occupancy and transcriptional targets in primary islets, leading to the identification of a number of Pdxl targets involved in maintaining critical functions of and potentially the biogenesis of the endoplasmic reticulum (ER), the subcellular organelle responsible for the facilitation of protein folding, disulfide bond formation and the transport to the Golgi of proteins destined for secretion. Optimal function of the ER and coordination of its capacity with protein synthesis and the load of unfolded and misfolded proteins is critically important in highly secretory cells such as B cells. Impairment of ER function results in impaired insulin secretion, ER stress, and eventually programmed cell death if the stress cannot be resolved through proper activation of the unfolded protein response (UPR). We hypothesize that Pdx1 regulates ER biogenesis and translation and that Pdx1 overexpression can promote islet compensation in animal models of diet-induced insulin resistance and diabetes. We further postulate that Pdx1 partners with the TALE homeodomain factor Meis3 to regulate at least a subset ofPdxl target genes involved in lineage allocation and beta cell survival and function. Our Specific Aims are: (1) To determine whether Pdxl regulates ER biogenesis and mRNA translation, (2) To determine if Pdxl over-expression preserves beta cell survival and function in models of insulin resistance and diabetes, and (3) To determine whether the Pdxl partner, Meis3, regulates islet development and function. Addressing these Aims will provide critical insight into the process of islet compensation that goes awry during the progression of type 2 diabetes. RELEVANCE (See instructions): Diabetes affects over 23 million individuals in the US and well over 150 million woridwide, with complications involving multiple organ systems, making it a formidable medical and public health issue. The natural history of diabetes depends in large part on the adaptation of pancreatic li-cells to meet the increased demand for insulin that results from insulin resistance. Targeting beta cell growth and/or function represents an important approach to develop novel therapies for diabetes.